tbuckley/cabot-search huggingface dataset:
IMMU-09. IDENTIFICATION OF A NEW THERAPEUTIC ANTIGEN FOR GLIOBLASTOMA USING A MONOCLONAL ANTIBODY LIBRARY FROM PATIENT-DERIVED TUMOR SPHERES
Authors: Hideki Kuroda, Noriyuki Kijima, Tetsuro Tachi, Koki Murakami, Ryuichi Hirayama, Yoshiko Okita, Naoki Kagawa, Naoki Hosen, Haruhiko Kishima
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) has a poor prognosis despite intensive treatment by surgery, radiation, and chemotherapy, thus new treatment strategies are urgently needed. Various innovative cancer therapies targeting cancer-specific cell surface antigens, such as chimeric antigen receptor T cell therapy, are developed and more cell surface antigens that is highly specific for GBM cells are needed. Although extensive transcriptome analyses or proteomic analysis of GBM cells were performed, few transcripts specific for GBM cells have been identified. However, GBM cell-specific antigen epitopes formed by post-translational modifications of proteins may have been missed by transcriptome or proteomic analysis, and could still be discovered by thoroughly searching for cancer-specific monoclonal antibodies. In this study, we aim to identify GBM-specific antigens using a monoclonal antibody library from patient-derived tumor spheres. Approximately 25,000 monoclonal antibody-producing hybridomas were establishment using Balb/c mice and patient derived tumor spheres. Among them, two antibodies that bind to glioblastomas and not to normal brain cells were selected and we identified the antigen by the expression cloning method. The antigen is a cell adhesion molecule and has been reported to be involved in the progression of solid tumors and is expected to be a tumor-specific antigen. These results indicate that the strategy shown in this study is useful for identifying antigens that are potentially useful as targets for GBM therapy.
PATH-53. ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA WITH BEND5-NTRK2 FUSION IN A YOUNG ADULT WITH A HISTORY OF CRANIAL RADIATION FOR CHILDHOOD RHABDOMYOSARCOMA
Authors: Julie Fischer, Andrea Gilbert, Shafqat Shah
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare subset of circumscribed astrocytic glioma. While PXA typically has a favorable prognosis, anaplastic (WHO Grade III) PXA (aPXA) has a poorer prognosis. Molecular analysis of PXA often reveals BRAF mutations or CDKN2A/B homozygous deletions. NTRK fusions have been identified in a few cases of pediatric gliomas including PXA. BEND-5 gene alterations have been rarely reported in CNS tumors such as glioblastoma but have not been previously reported in PXA. Case Presentation The patient is a 24-year-old female with history of nasopharyngeal embryonal rhabdomyosarcoma treated with chemotherapy and radiation at age 3. She was tested for Li-Fraumeni Syndrome and was reportedly negative. One year ago, she presented with visual changes and was found to have an occipital aPXA. She underwent a gross total resection but declined further treatment with radiation. Next-generation sequencing (NGS) identified a BEND5-NTRK2 fusion, and she began treatment with Larotrectinib. Serial MRI scans have shown no evidence of disease recurrence. Discussion Pediatric patients are at increased risk for glioma after radiation which is age- and dose/volume-dependent. Radiation-induced gliomas are typically higher grade, present in atypical sites, and have a poor prognosis. Development of PXA following radiation is rare but has been reported. Our patient was diagnosed with aPXA almost 20 years after initial treatment for rhabdomyosarcoma. Her aPXA exhibited a BEND5-NTRK2 fusion and lacked classical BRAF alterations and CDKN2A/B deletions that are present in de novo cases. A Neuro-Onc Panel did not identify her fusion or include testing for BEND5 alterations. However, an expanded RNA Exome Fusion Panel NGS identified a unique fusion, which opened her up to targeted treatment with an NTRK inhibitor. Our patient is now 1 year from resection without disease progression on larotrectinib. This case highlights the importance of expanded NGS testing, particularly in rare tumors.
SURG-45. THE EFFECT OF STAPEDECTOMY IN POSTOPERATIVE OUTCOME OF SUPERIOR SEMICIRCULAR CANAL DEHISCENCE: A CASE SERIES OF 349 REPAIRS
Authors: Lisette Torres, Sanah Vohra, Mahlet Mekonnen, Aryan Pandey, Ariana Chow, Quinton Gopen, Isaac Yang
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Superior Semicircular Canal Dehiscence (SSCD) is a pathology of the otic capsule, in which, a “third mobile window” is formed on the osseous labyrinth surrounding the superior semicircular canal. Otosclerosis, another otic capsule pathology, can occur concurrently, therefore obscuring the symptoms seen in patients with SSCD. It is currently unknown whether the surgical procedures to treat otosclerosis such as stapedectomy can affect symptom resolution in patients following SSCD repair. Objective: To examine the association between post-SSCD repair symptom resolution and history of stapedectomy. METHODS A single institution retrospective review was conducted to evaluate post-operative symptom resolution in patients undergoing SSCD repair from 2011-2021. 349 SSCD repairs performed in a cohort of 279 patients were included, and among those were 10 patients with a history of stapedectomy. A p-value &amp;lt; 0.05 was considered statistically significant. RESULTS A total of 349 surgical repairs were analyzed. The patient population was composed of 63% female and 37% male with patient ages’ ranging from 13-84 years. Patients were divided into two different cohorts based on their history of stapedectomy. We compared these cohorts looking at their post-SSCD repair symptom changes and found no statistically significant differences between patients with and without history of stapedectomy. We also compared pre- and post-operative symptoms amongst the 10 patients with a history of stapedectomy and found no statistically significant differences in symptom resolution post-SSCD repair. Post-operative symptoms analyzed included amplification (p = 0.2), aural fullness (p = 0.2), autophony (p = 0.8), disequilibrium/imbalance (p = 0.8), dizziness (p = 0.3), headache (p = 0.7), hearing loss (p = 1), hyperacusis (p = 1), tinnitus (p = 0.4), and vertigo (p = 0.3). CONCLUSIONS With respect to symptom resolution post-SSCD repair, there were no significant differences between patients with and without a history of stapedectomy. Hence, previous stapedectomy surgery should not be considered an adverse condition to SSCD repair, with similar rates of improvement after SSCD surgery.
Long-Term Blood Pressure Control After Hypertensive Pregnancy Following Physician-Optimized Self-Management
Authors: Jamie Kitt, Rachael Fox, Annabelle Frost, Milensu Shanyinde, Katherine Tucker, Paul A. Bateman, Katie Suriano, Yvonne Kenworthy, Annabelle McCourt, William Woodward, Winok Lapidaire, Miriam Lacharie, Mauro Santos, Cristian Roman, Lucy Mackillop, Christian Delles, Basky Thilaganathan, Lucy C. Chappell, Adam J. Lewandowski, Richard J. McManus, Paul Leeson
Journal: JAMA (2023)

Importance Pregnancy hypertension results in adverse cardiac remodeling and higher incidence of hypertension and cardiovascular diseases in later life. Objective To evaluate whether an intervention designed to achieve better blood pressure control in the postnatal period is associated with lower blood pressure than usual outpatient care during the first 9 months postpartum. Design, Setting, and Participants Randomized, open-label, blinded, end point trial set in a single hospital in the UK. Eligible participants were aged 18 years or older, following pregnancy complicated by preeclampsia or gestational hypertension, requiring antihypertensive medication postnatally when discharged. The first enrollment occurred on February 21, 2020, and the last follow-up, November 2, 2021. The follow-up period was approximately 9 months. Interventions Participants were randomly assigned 1:1 to self-monitoring along with physician-optimized antihypertensive titration or usual postnatal care. Main Outcomes and Measures The primary outcome was 24-hour mean diastolic blood pressure at 9 months postpartum, adjusted for baseline postnatal blood pressure. Results Two hundred twenty participants were randomly assigned to either the intervention group (n = 112) or the control group (n = 108). The mean (SD) age of participants was 32.6 (5.0) years, 40% had gestational hypertension, and 60% had preeclampsia. Two hundred participants (91%) were included in the primary analysis. The 24-hour mean (SD) diastolic blood pressure, measured at 249 (16) days postpartum, was 5.8 mm Hg lower in the intervention group (71.2 [5.6] mm Hg) than in the control group (76.6 [5.7] mm Hg). The between-group difference was −5.80 mm Hg (95% CI, −7.40 to −4.20; P &amp;amp;lt; .001). Similarly, the 24-hour mean (SD) systolic blood pressure was 6.5 mm Hg lower in the intervention group (114.0 [7.7] mm Hg) than in the control group (120.3 [9.1] mm Hg). The between-group difference was −6.51 mm Hg (95% CI, −8.80 to −4.22; P &amp;amp;lt; .001). Conclusions and Relevance In this single-center trial, self-monitoring and physician-guided titration of antihypertensive medications was associated with lower blood pressure during the first 9 months postpartum than usual postnatal outpatient care in the UK. Trial Registration ClinicalTrials.gov Identifier: NCT04273854
CTIM-13. PHASE I CLINICAL TRIAL OF ONCOLYTIC HSV-1 M032, A SECOND-GENERATION VIRUS ARMED TO EXPRESSED IL-12, FOR THE TREATMENT OF ADULT PATIENTS WITH RECURRENT OR PROGRESSIVE MALIGNANT GLIOMA
Authors: Dagoberto Estevez-Ordonez, John Stein, Pedram Maleknia, Carlos Gallegos, Travis Atchley, Nicholas Laskay, Jennifer Clements, Mina Lobbous, Jianmei Leavenworth, Kristen Riley, Inmaculada Aban, Anna Sorace, Rati Chkheidze, Burt Nabors, James Markert
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Effective treatment options are limited for patients diagnosed with malignant glioma, and outcomes remain very poor. Recurrence and progression rates are universal. Preclinical data showed that a second-generation oncolytic herpes virus (oHSV) with selective replication and armed to induce IL-12 expression was a more effective anti-glioma agent than the first-generation oHSV. METHODS We conducted an open-label, dose-escalating phase I trial designed to determine the safety and tolerability of intratumoral injection of the M032 virus in patients with recurrent or progressive MG. Patients underwent stereotactic placement of intratumoral catheters. The following day, M032 was infused over a period of 6 hours. Primary endpoint was to determine safety and maximum tolerated dose (maximal planned dose of 109 PFU). Dose elevations were made using a modified Continual Reassessment Method. RESULTS Twenty-one patients with recurrent MG ages 19 to 71 received M032 (16 Males, 5 Females). Fourteen patients had IDH wild-type tumors, and eighteen patients had unmethylated MGMT status. Four grade 1, two grade 2, two grade 3, and two grade 4 adverse events were identified as possibly related to M032. Both grade 3 and grade 4 adverse events possibly related to M032 occurred in a single patient on the 108 PFU cohort. No serious adverse events at the maximal plan dose were attributed to M032. Median post-treatment survival was 9.38 months (95% CI, 7.57 to 12.95). 2 participants were still alive following treatment. CONCLUSIONS Intratumoral M032 had an acceptable adverse-event profile. We observed two grade 3 and two grade 4 adverse events in a patient with a large tumor prompting an amendment to tumor size inclusion criteria. No dose-limiting toxicity occurred at the maximum dose. Preliminary evidence suggests favorable response in some patients with recurrent or progressive MG. Careful selection of patients is needed when considering treatment with M032 (ClinicalTrials.gov number, NCT02062827).
DDDR-24. SINGLE-CELL FUNCTIONAL TISSUE PROFILING IDENTIFIES PROMISING CANDIDATES FOR DRUG REPURPOSING AGAINST GLIOBLASTOMA
Authors: Tobias Weiss, Sohyon Lee, Marcel Buehler, Julien Mena, Zuzanna Lottenbach, Rebekka Wegmann, Michael Bihl, Miaomiao Sun, Sandra Goetze, Audrey van Drogen, Flavio Vasella, Bernd Wollscheid, Berend Snijder, Michael Weller
Journal: Neuro-Oncology (2023)

Abstract There remains an unmet need for novel treatment strategies against glioblastoma that are more effective than the current standard of care. However, the complex tumor microenvironment and genetic heterogeneity of these tumors require novel technologies enabling high-throughput assessment of cellular responses to treatments on a functional level in complex tumor samples with an intact cellular microenvironment. Here, we used a novel single-cell functional tissue profiling platform based on high—throughput microscopy followed by computer vision and machine learning algorithms to screen 70 clinically-approved drugs with good blood-brain-barrier penetration in 35 glioblastoma patient samples that were freshly obtained from surgery. This revealed prognostically relevant subtypes of glioma cell morphologies and promising candidates for drug repurposing. Among the drugs with potent anti-glioma activity, we identified the antidepressant Vortioxetine, that had strong anti-glioma activity across patients independent of the promoter methylation status of O6-methylguanine-DNA methyltransferase (MGMT). Complementrary in vitro studies using patient-derived glioma cell lines and orthotopic glioma xenograft mouse models confirmed the strong anti-glioma activity of Vortioxetine, leading to a notable fraction of long-term surviving mice. Mechanistically, multiplexed transcriptomics and proteomics unveiled that Vortioxetine induced an upregulation of the Activator protein 1 (AP-1) transcription factor family, along with the B-cell translocation gene (BTG) tumor suppressor genes. These findings serve as the cornerstone for future clinical applications of the single-cell functional tissue profiling platform and the potential clinical translation of Vortioxetine as a promising drug-repurposing candidate for glioblastoma patients.
EPID-10. CNSONTRK STUDY: CLINICAL CHARACTERISTICS AND OUTCOME OF CENTRAL NERVOUS SYSTEM TUMORS HARBORING NTRK GENE FUSIONS
Authors: Audrey-Anne Lamoureux, Michael Fisher, Lauriane Lemelle, Elke Pfaff, Bram De Wilde, Stefan Pfister, Dominik Sturm, Daniel Orbach, Scott Raskin, Alexander Drilon, Michal Zapotocky, Marc Barritault, Pierre Leblond, Uri Tabori, Cynthia Hawkins, Jordan Hansford, Craig Erker, Nicholas Gottardo, Dorte Nørøxe, Hiroaki Goto, David Ziegler, Yen-Lin Liu, Eugene Hwang, Ana Aguilar-Bonilla, Sylvia Cheng, Chantel Cacciotti, Maura Massimino, Paul Wood, Lindsey Hoffman, Alvaro Lassaletta, Nicolas Gerber, Mariella Spalato Ceruso, Anne Bendel, Christina Coleman Abadi, Sabine Mueller, Dolly Aguilera, Nathan Robison, Katrina O’Halloran, Samuel Abbou, Birgit Geoerger, Ingrid Øra, Christopher Moertel, Evangelia Razis, Romuald Seizeur, Matthew Clarke, François Doz, Theodore Laetsch, Sébastien Perreault, Benjamin Ellezam, Mélanie Alves
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND TRK fusions are detected in less than 2% of central nervous system (CNS) tumors. There are limited data on the clinical course of affected patients. METHODS We conducted an international retrospective cohort study of patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, TRK gene fusion, treatment modalities and outcomes. The growth modulation index (GMI) was calculated as a ratio of time to progression with TRK inhibitors to time to progression with the prior line of therapy. RESULTS 119 patients with TRK fusion-driven primary CNS tumors were identified. Median age at diagnosis was 4.5 years (range 0.0–78.3); 101 (85.6%) were &amp;lt; 18 and 45.3% were &amp;lt; 3 years of age. The most frequent tumor location was hemispheric (63.8%). Tumor types included 68 high-grade gliomas (HGG; 57.1%), 33 low-grade gliomas (LGG; 27.7%), 5 embryonal tumors (4.2%) and 13 others (10.9%). Median follow-up was 38.5 months (range 0.03–229.3). Pediatric patients had a better prognosis with a median OS of 185.5 months compared to 24.8 months in adults (p&amp;lt; .0001). Patients with LGG also had a better outcome with median OS that was not reached for LGG compared to 99.5 months for HGG and 38.5 months for embryonal tumors (p=0.0012). Out of 16 evaluable treatment regimens with larotrectinib an objective response was reported in 11 (11/16 (68.8%)-4 CR, 5 PR and 2 MR) compared to 38.1% for non-targeted treatment regimens (24/63 (38.1%)-10 CR, 13 PR and 1 MR). The GMI was 2.11 for pediatric patients treated with larotrectinib. CONCLUSIONS We report a large cohort of patients with TRK fusion-driven primary CNS tumors. Children with LGG glioma had a favorable outcome compared to adult and HGG. Larotrectinib appears to be associated with a better response rate and longer duration of response compared to non-targeted therapy.
BIOM-58. ZERO-WASTE MOLECULAR DIAGNOSTICS FROM BIOPSY NEEDLE WASHES
Authors: Jack Wadden, Vishal John, Michael Niculcea, Seongbae Kong, Rayan Aittaleb, Rodrigo Cartaxo, Kait Verbal, Amy Bruzek, Suresh Magge, Sridevi Yadavilli, Nir Erez, Noa Furth, Efrat Shema, Neena Marapudi, Jason Heth, Wajd Al-holou, Hugh Garton, Javad Nazarian, Carl Koschmann
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Brain tumor classification has increasingly integrated molecular diagnostics into official criteria. However, biopsy tissue is limited due to the small quantity acquired in eloquent areas of the brain and is, therefore, usually earmarked for histology. We have identified that the fluid used to wash biopsy needles contains excess tumor material that can be diagnostically useful. Characterization of this non-zero-sum waste material provides an opportunity for improvement in the diagnosis and treatment for brain tumor patients. METHODS For suspected or established high grade brain tumor biopsies (n = 37 across a multi-institutional cohort at submission), neurosurgeons were instructed to save fluid used to wash biopsy needles. Samples were processed and characterized in a variety of methods to establish diagnostic utility including (1) cell-free DNA isolation and targeted panel sequencing (n = 13), (2) isothermal amplification of cell-free DNA from raw wash water for rapid diagnostics (n = 2), (3) cell-line generation (n = 24) and, (4) cell-free mutant protein capture and quantification (n = 9). RESULTS (1) 13 wash samples were considered for cf-tDNA extraction and Illumina TruSight Oncology 500 panel sequencing (with extracted DNA ranging from 20ng-40ug). In 2 returned cases (11 pending), concordance was 100% with clinical targeted panel sequencing where panels overlapped. (2) One case suspected of harboring H3K27M was subjected to targeted, loop-mediated isothermal amplification and Oxford Nanopore real-time sequencing, confirming an H3.3K27M diagnosis (11.8% allele fraction) within 1hr35min of receipt of sample from the operating room. (3) 5 cases resulted in primary cell culture generation (4) A novel single-molecule mutant protein quantification technique was performed on 9 cases. RESULTS from all analyses and concordance with outstanding sequencing will be presented. CONCLUSION We demonstrate that biopsy byproducts contain enough high-quality tumor-derived material to perform a variety of useful diagnostics with the potential to have immediate translational impact on standard of care.
CTIM-03. LONG TERM FOLLOW-UP OF A PROSPECTIVE SAFETY AND TOXICITY STUDY OF IMMUNE CHECKPOINT INHIBITOR THERAPY INITIATED 8 DAYS PRIOR TO RADIOSURGERY FOR MELANOMA BRAIN OR SPINE METASTASIS
Authors: Lawrence Kleinberg, Xiaobu Ye, William Sharfman, Christopher Jackson, Kristin Redmond, Chetan Bettegowda, Kelly Szajna, Whitney Isennock, Jessica Wollett, Evan Lipson, Michael Lim
Journal: Neuro-Oncology (2023)

Abstract We conducted a pilot study of checkpoint inhibitor (ICI) therapy followed in eight days(+/- 2) by initiation of SRS for brain or spine metastasis based on murine experiments of pre-SRS initiation of ICI. Alternative time intervals would be tested If there was &amp;gt;33% dose limiting toxicity(DLT) &amp;gt;Gr3 by CTCAE 4.0 within 12 weeks of treatment initiation (excluding Gr3 tumor flare, rash, immune reaction resolving to gr1 in &amp;lt;28 days). Initially ipilimumab was used, with protocol change to nivolumab as standard of care evolved. Treatment continued until DLT, progression, or clinical decision to end therapy. Dosing and timing of subsequent cycles were by institutional preference. Eligibility included melanoma with newly diagnosed unirradiated brain or spine metastasis, at least one &amp;gt;3 mm, no autoimmune diseases. Twenty-one patients enrolled, 17(81%) treated with nivolumab, 20(95%) had brain metastasis. The median baseline number of brain metastasis was 2(1-9). 7 subjects (33%) had only one brain met. Seven subjects(33%) were free of extra-CNS metastasis at baseline; 5(23%) had 1-5 systemic metastasis (oligometaststic), and 9 subjects(43%) had 6 or more systemic metastasis. Median number of cycles of checkpoint inhibitor therapy was 3 (1-37). The grade 3 toxicities (no grade 4 and 5) with possible, probable, or definite attribution to ipilimumab were colitis(4.8%), diarrhea(9.5%), fatigue(4.8%), muscle weakness (4.8%), and headache(4.8%). One subject had colitis as a DLT. No toxicity &amp;gt;3 or above was associated with nivolumab. Estimated median overall survival was 37.4 months, within minimum f/u of 8 surviving patients of 40 months (40-68). Three-year OS rate was 52%. Checkpoint inhibitor therapy initiated 8 days prior to SRS was safe and survival outcome is favorable. Peripheral blood Immune correlative studies are pending. Prospective data is needed to define optimal safety, timing, and outcome of concurrent checkpoint inhibitor therapy and radiosurgery for melanoma metastatic to the brain.